PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation

被引：91

作者：

Heo, Kyung-Sun ^{[1
]}

Lee, Hakjoo ^{[1
]}

Nigro, Patrizia ^{[1
]}

Thomas, Tamlyn ^{[1
]}

Le, Nhat-Tu ^{[1
]}

Chang, Eugene ^{[1
]}

McClain, Carolyn ^{[1
]}

Reinhart-King, Cynthia A. ^{[2
]}

King, Michael R. ^{[2
]}

Berk, Bradford C. ^{[1
]}

Fujiwara, Keigi ^{[1
]}

Woo, Chang-Hoon ^{[1
]}

Abe, Jun-ichi ^{[1
]}

机构：

[1] Univ Rochester, Aab Cardiovasc Res Inst, Rochester, NY 14642 USA

[2] Cornell Univ, Dept Biomed Engn, Ithaca, NY 14853 USA

来源：

JOURNAL OF CELL BIOLOGY | 2011年 / 193卷 / 05期

基金：

美国国家卫生研究院;

关键词：

PROTEIN-KINASE-C; NITRIC-OXIDE SYNTHASE; SIGNAL-REGULATED KINASE-5; LAMINAR SHEAR-STRESS; KAPPA-B ACTIVATION; PEROXYNITRITE FORMATION; LESION FORMATION; GENE-EXPRESSION; GROWTH ARREST; CELL-DEATH;

D O I：

10.1083/jcb.201010051

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Atherosclerosis is readily observed in regions of blood vessels where disturbed blood flow (d-flow) is known to occur. A positive correlation between protein kinase C zeta (PKC zeta) activation and d-flow has been reported, but the exact role of d-flow-mediated PKC zeta activation in atherosclerosis remains unclear. We tested the hypothesis that PKC zeta activation by d-flow induces endothelial cell (EC) apoptosis by regulating p53. We found that d-flow-mediated peroxynitrite (ONOO.) increased PKC zeta activation, which subsequently induced p53 SUMOylation, p53-Bcl-2 binding, and EC apoptosis. Both d-flow and ONOO. increased the association of PKC zeta with protein inhibitor of activated STATy (PIASy) via the Siz/PIAS-RING domain (amino acids 301-410) of PIASy, and overexpression of this domain of PIASy disrupted the PKC zeta-PIASy interaction and PKC zeta-mediated p53 SUMOylation. En face confocal microscopy revealed increases in nonnuclear p53 expression, nitrotyrosine staining, and apoptosis in aortic EC located in d-flow -areas in wild-type mice, but these effects were significantly decreased in p53(-/-) mice. We propose a novel mechanism for p53 SUMOylation mediated by the PKC zeta-PIASy interaction during d-flow-mediated EC apoptosis, which has potential relevance to early events of atherosclerosis.

引用

页码：867 / 884

页数：18

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